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. 2021 Sep 14;3(3):fcab207.
doi: 10.1093/braincomms/fcab207. eCollection 2021.

Genome sequencing identifies rare tandem repeat expansions and copy number variants in Lennox-Gastaut syndrome

Farah Qaiser  1   2   3 , Tara Sadoway  3 , Yue Yin  2 , Quratulain Zulfiqar Ali  3 , Charlotte M Nguyen  1   2 , Natalie Shum  1   2 , Ian Backstrom  2 , Paula T Marques  3 , Sepideh Tabarestani  3 , Renato P Munhoz  4   5 , Timo Krings  6   7 , Christopher E Pearson  1   2 , Ryan K C Yuen  1   2 , Danielle M Andrade  3   4   8
Affiliations

Genome sequencing identifies rare tandem repeat expansions and copy number variants in Lennox-Gastaut syndrome

Farah Qaiser et al. Brain Commun. .

Abstract

Epilepsies are a group of common neurological disorders with a substantial genetic basis. Despite this, the molecular diagnosis of epilepsies remains challenging due to its heterogeneity. Studies utilizing whole-genome sequencing may provide additional insights into genetic causes of epilepsies of unknown aetiology. Whole-genome sequencing was used to evaluate a cohort of adults with unexplained developmental and epileptic encephalopathies (n = 30), for whom prior genetic tests, including whole-exome sequencing in some cases, were negative or inconclusive. Rare single nucleotide variants, insertions/deletions, copy number variants and tandem repeat expansions were analysed. Seven pathogenic or likely pathogenic single nucleotide variants, and two pathogenic deleterious copy number variants were identified in nine patients (32.1% of the cohort). One of the copy number variants, identified in a patient with Lennox-Gastaut syndrome, was too small to be detected by chromosomal microarray techniques. We also identified two tandem repeat expansions with clinical implications in two other patients with Lennox-Gastaut syndrome: a CGG repeat expansion in the 5'untranslated region of DIP2B, and a CTG expansion in ATXN8OS (previously implicated in spinocerebellar ataxia type 8). Three patients had KCNA2 pathogenic variants. One of them died of sudden unexpected death in epilepsy. The other two patients had, in addition to a KCNA2 variant, a second de novo variant impacting potential epilepsy-relevant genes (KCNIP4 and UBR5). Overall, whole-genome sequencing provided a genetic explanation in 32.1% of the total cohort. This is also the first report of coding and non-coding tandem repeat expansions identified in patients with Lennox-Gastaut syndrome. This study demonstrates that using whole-genome sequencing, the examination of multiple types of rare genetic variation, including those found in the non-coding region of the genome, can help resolve unexplained epilepsies.

Keywords: ATXN80S; DIP2B; Lennox–Gastaut syndrome; tandem repeats; whole-genome sequencing.

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Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Annotated pedigrees for patients with a variant in KCNA2. The patient’s clinical phenotype is further detailed in Table 2.
Figure 2
Figure 2
Detection of a CGG expansion in DIP2B in patient 4. (A) An annotated family pedigree for patient 4 with LGS, who presented with seizures and ID. The father has a history of seizures. (B) Schematic shows the design, and southern blot confirmation of ∼12 and 128 CGG repeat units in the 5’UTR of DIP2B in patient 4.
Figure 3
Figure 3
Detection of a CTG expansion in ATXN80S in patient 6. (A) An annotated family pedigree for patient 6, who presented with LGS. There is no family history of epilepsy. (B) and (C) display fragment length analyses of this TR locus in the patient 6 and their mother (6A), respectively, visualized using PeakScanner 2. The x-axis represents the fragment length (in bp) and the y-axis is a scale of peak intensity.
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